MACROPHAGE GROWTH: ROLE OF COLONY-STIMULATING FACTOR

巨噬细胞生长：集落刺激因子的作用

• 批准号: 2062230
• 负责人: BEN D CHEN
• 金额: $ 13.54万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1995-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2062230
• 关键词: alveolar macrophages; bioassay; cell differentiation; cell growth regulation; cell population study; colony stimulating factor; cytokine receptors; flow cytometry; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; interleukin 1; laboratory mouse; laboratory rat; macrophage; monoclonal antibody; paracrine; receptor expression; tissue /cell culture

The proliferation and differentiation of hematopoietic cells are dependent on the continuous presence of a group of growth factors known as colony-stimulating factors (CSFs). At least three known CSFs, Multi-CSF (IL-3), GM-CSF and M-CSF are involved in this process. Recent studies indicate that the action of CSFs is not restricted to hemopoietic precursor cells but includes the more mature macrophage progenitors, known as macrophage colony-forming cells (M-CFC), outside the bone marrow as well. Additionally, CSFs stimulate several functional aspects of mature macrophages, not related to proliferative activity. Murine alveolar M-CFC represent a unique cell population in that they can be induced by all three types of CSFs, either alone or in combination, to undergo clonal growth in vitro. This observation supports the concept that CSFs also play a key role in the regulation of macrophage production a the local level presumably through a paracrine mechanism. In this applicAtion, we will test this hypothesis and define the roles of CSF's in this process using murine alveolar macropohages as our working model. First, using reciprocal clone transfer experiments we will study the mechanisms in which various CSF's interact in the control of alveolar macrophage proliferation and differentiation and define the roles CSF's have in the generation of macrophage heterogeneity. We will then determine whether subsets of alveolar M-CFC exist and what is the relationship between these cells populations in terms of CSF receptor expression during their differentiation process. CSF- receptor bearing cells will be isolated and analyzed by using specific Anti-receptor antibodies and fluorescence-activated cell sorter (FACS) as well as autoradiography using iodinated CSFs. Next, we will study the ontogency of alveolar M-CFC in mice under both normal and pathologic conditions and determine whether they represent local macrophage progenitor cells with self-renewal potential. Finally, we will study the in vivo effect of recombinant CSFs as well as interleukin 1 (IL-1) on the production of alveolar macrophAges and local progenitor cells in both normal and irradiated or chemotherapy treated mice. The effect of CSFs in the regulation of functional activity of mature macrophages will also be examined.

造血细胞的增殖和分化是 依赖于一组生长因子的持续存在 被称为集落刺激因子(CSF)。至少有三个已知 CSF、多粒细胞集落刺激因子(IL-3)、粒-巨噬细胞集落刺激因子(GM-CSF)和巨噬细胞集落刺激因子(M-CSF)参与其中 进程。最近的研究表明，CSF的作用不是 仅限于造血祖细胞，但包括更多 成熟的巨噬细胞前体细胞，称为巨噬细胞集落形成 细胞(M-cfc)，也在骨髓外。此外，CSF 刺激成熟巨噬细胞的几个功能方面，而不是 与增殖活动有关。 小鼠肺泡巨噬细胞集落刺激因子代表了一种独特的细胞群 它们可以由所有三种类型的CSF单独或在 结合，在体外进行克隆生长。这一观察结果 支持这样一个概念，即CSF也在 巨噬细胞产生的调节可能是局部水平的 通过旁分泌机制。在此应用程序中，我们将测试 这一假设并定义了脑脊液在这一过程中的作用 以小鼠肺泡巨噬细胞为工作模型。首先，使用 相互克隆转移实验，我们将研究其机制 其中不同的脑脊液相互作用对肺泡的控制 巨噬细胞增殖和分化及其作用的确定 脑脊液在巨噬细胞的生成中具有异质性。我们会 然后确定是否存在肺泡M-cfc亚群，以及存在什么 从脑脊液的角度看这些细胞群之间的关系 受体在分化过程中的表达。脑脊液- 受体承载细胞的分离和分析将使用 特异性抗受体抗体与荧光激活细胞 分类器(FACS)以及使用碘化CSF的放射自显影。 接下来，我们将研究肺泡M-CFCs在小鼠体内的致病作用。 正常和病理状态，并确定它们是否 代表具有自我更新功能的局部巨噬祖细胞 潜力。最后，我们将研究其体内效应。 重组CSF和白介素1(IL-1)对生产的影响 肺泡巨噬细胞和局部祖细胞的表达 以及接受过辐射或化疗的小鼠。社会保障基金的作用 在调节成熟巨噬细胞的功能活动中 也要接受检查。